This invention relates to methods of enhancing the biodistribution in a mammalian subject. More specifically this invention relates to the use of monoclonal antibodies for localization, detection, and treatment of lesions, including tumors, in humans.
The diagnostic and therapeutic use of radioactively labeled antibodies specific to substances produced by or associated with tumors to detect or locate tumors is recognized.
Carcinoembryonic antigen (CEA) is an example of an antigen or marker substance produced by tumor cells and associated with tumor cell membrane. Some of the CEA becomes separated from the tumor cell and progresses through the interstitial fluid and eventually reaches the circulation of the host.
Administration of antibody specific for CEA to a human or animal with a CEA-producing tumor results primarily in the antibody attaching to the CEA in circulation while some reaches the tumor site which contains the highest amount of antigen. Eventually if a steady state equilibrium can be reached, antibody will accumulate at the tumor.
U.S. Pat. No. 3,927,193 to Hansen et al. describes a method for determining the site of tumors which produce or are associated with CEA using labeled antibodies to CEA. U.S. Pat. No. 4,311,688 to Burchiel et al. describes the detection of cells that produce human chorionic gonadotropin (hCG) and compounds similar to the beta-chain of hCG by first administering anti-hCG or anti-hCG-beta and then administering radioactively labeled antibodies to anti-hCG-beta or anti-hCG. U.S. Pat. No. 4,331,647 to Goldenberg describes both the detection of tumors using mixtures of radiolabeled antibody fragments specific to tumor-associated markers and tumor radiotherapy using antibody fragments labeled with radiotherapeutically effective radioisotopes. U.S. Pat. No. 4,478,815 to Burchiel et al. likewise describes the use of radio-labeled antibody fragments to detect tumors producing hCG or other tumor associated antigen.
A major problem encountered in the use of radiolabeled antibodies to detect or treat tumors is the uptake or accumulation of radioactivity caused by radiolabeled antibodies, antibody fragments, or their metabolites in the blood pool, in interstitial fluids, or other tissues such as the liver and spleen. The isotopes most frequently chosen for radioimaging are the iodine isotopes (I-123, I-125, and I-131) and indium-111. While indium-111 has several advantages over the most commonly used iodine isotope, I-131, the use of indium-111 as a label for monoclonal or other antibodies has the disadvantage of a marked uptake in normal liver.
If administered antibody is radiolabeled and there is a substantial amount of marker substance such as CEA available in the circulation, then antibody-antigen complexes formed will be cleared rapidly, primarily by the liver and spleen. Such uptake of radioactivity in these organs, especially the liver, predominates over any uptake by tumor and significantly reduces the resolution of tumor localization using radiolabeled antibodies. The amount of labeled antibody in the blood will drop rapidly due primarily to liver uptake and the ratio of uptake in liver as compared to that of the blood (L/B ratio) is very high. The detection or localization of lesions located in or near the liver is consequently particularly difficult because of the increased uptake of radiolabeled substances.
In an effort to solve the general problem of accumulated radioactivity in the body, U.S. Pat. No. 4,348,376 to Goldenberg, describes the localization of tumors associated with CEA by concurrently administering both a radiolabeled antibody specific to CEA, and a background compensating material, normal immunoglobulin from the same or different species as that used to prepare the antibody, which is radiolabeled with a different radioisotope of the same element used to label the antibody to CEA. The level of radioactivity of the labeled normal immunoglobulin is used to determine the distribution of background radioactivity due to non-targeted specific antibody, which background distribution is then subtracted from the total activity. U.S. Pat. No. 4,444,744 to Goldenberg similarly describes a method for detecting other tumor-associated antigens.
U.S. Pat. No. 4,460,561 to Goldenberg describes a method of tumor therapy wherein thermal neutrons excite a boron-10 isotope-containing antibody which has been localized by detection of an attached radioisotope label.
A further method of diminishing nontumor-associated antibody is described in Goldenberg, PCT Pat. No. WO9500522. A radiolabeled tumor-specific antibody is injected into the subject, and at a time after injection of the antibody sufficient to permit maximum selective uptake thereof by the tumor, a second, non-radiolabeled antibody specific against the first radiolabeled antibody is injected. The second antibody binds with an amount of labeled antibody not associated with tumor tissue such that the level of circulating (nontumor-associated) radiolabeled antibody is decreased. The mechanism of liver uptake of indium-labeled antibodies is not yet known. Accumulation of indium-111 in liver tissue is seen in both tumor and non-tumor bearing mice. However, tumor bearing mice have significantly higher liver levels of radioactivity, up to 40-50% injected dose/gram (ID/g), than non-tumor bearing mice, 6-10% ID/g. In the nude mice model, the size of the tumor directly affects the liver uptake of indium-111 and inversely affects tumor uptake of indium-111. Williams, L. E., et al., J. Nucl. Med. 29:103-109 (1988); Hagan, P. L., et al., J. Nucl. Med. 24:422-427 (1986); Philben, V. J., et al., Cancer 57:571-576 (1986); Pedley, R. B., et al., Eur. J. Nucl. Med. 13:197-202 (1987).
In the following description of the present invention, the term "biodistribution" refers to the distribution of antibody in a subject to which antibody has been administered. By contrast, "uptake" refers to the quantity of antibody in a given tissue. The terms "lesion-associated marker substance", "marker substance", or "marker" refers to a substance produced by or associated with a lesion and for which an administered antibody is specific. A lesion is an abnormal change in the structure of an organ or part due to injury or disease, e.g., a tumor.